3-unsubstituted steroids of the pregnane series



United States Patent M 3,053,859 3-UNSUBSTITUTED STEROIDS OF THEPREGNANE SERIES Albert Bowers and James C. Orr, Mexico City, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation ofPanama No Drawing. Filed Aug. 22, 1961, Ser. No. 133,068 25 Claims. (Cl.260-3973) od f? I 3,053,859 Patented Sept. 11, 1962 g5 WI T In the aboveformulas, R represents hydrogen or methyl; R represents formyl (-CHO) orthe group -CH OR wherein R represents hydrogen or a hydrocarboncarboxylic acyl group of less than 12 carbon atoms. In the saturatedcompounds, R may be in the 20: or 25 position. The acyl group is derivedfrom hydrocarbon carboxylic acids containing less than 12 carbon atomswhich may be saturated or unsaturated, of straight, branched, cyclic orcyclic-aliphatic chain, aromatic and may be substituted by functionalgroups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxycontaining up to 12 carbon atoms, nitro, amino or halogen. Typical estergroups are the acetate, propionate, enanthate, benzoate,trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate,aminoacetate and B-chloropropionate.

The novel compounds represented by the above formulas are powerfulprogestational agents. They also exhibit anti-estrogenic,anti-gcnadotrophic and anti-androgenic activities. They are useful inthe treatment of premenstrual tension and lower cholesterol level inblood serum and the adrenal gland. In addition they have diureticproperties, being useful anti-aldosterone agents.

The novel compounds of the present invention which contain the formyl orhydroxymethyl group at C-2 in a steric configuration are prepared by aprocess illustrated by the following equation:

H mi VIII: X=

VII: X=O

In the above formulas, R has the same meaning as previously describedand Me represents the methyl group.

In practicing the process outlined above, the starting compoundallopregnan-BB-ol-ZO-one or the l9-nor deriva tive thereof (1) istreated with a glycol such as ethylene glycol in the presence ofp-toluenesulfonic acid to form the corresponding ZO-cycloethylenedioxyderivative to thus protect the ZO-keto group. Oxidation of this lastformed compound, preferably under Oppenauer conditions, affords thecorresponding 3-keto compound (II). Upon reaction of the thus formed-cycloethylenedioxyallopregnan-3-one or the 19-nor derivative with ethylformate, there is formed the respective Z-hydroxymethylene-20-cycloethylenedioXy-allopregnan-3-one derivative (III). This lattercompound is methylated, preferably with a solution of diazomethane in asuitable organic solvent, such as methylene chloride, to afford thecorresponding 2 -methoxymethylene 20cycloethylenedioxy-allopregnan-S-one derivative (IV). Upon reduction ofthis compound with lithium aluminum hydride, there is formed the3-desoxo compound (V) which upon treatment in a very mild acid mediumaffords the corresponding 2aforrnyl 20 cycloethylenedioxy allopregnanecompound (VI). Reduction of this latter derivative, preferably withsodium borohydride, furnishes the respective2a-hydroxymethyl-ZO-cycloethylenedioxy-allopregnane (VIII).

The protective cycloethylenedioxy moiety may be removed prior to thereduction with sodium borohydride by treatment with a mild acid to yieldthe 2a-formyl-allopregnan-ZO-one or l9-nor derivative thereof (VII)which in turn may be reduced to form the corresponding 20:-hydroxymethyl-allopregnan-ZO-one derivative (IX). The latter compoundmay also be prepared by removal of the cyclic ketal moiety from compoundVIII in the same manner as described above.

The preparation of the novel compounds of the present invention whichcontain the formyl or hydroxymethyl group at C-2 and 5 stericconfiguration or with ring A unsaturation are illustrated by thefollowing equation:

In the above equation, R and Me have the same meaning as heretoforedescribed.

"In practicing the process outlined above, the Z-methoxymethylenecycloethylenedioxy allopregnan 3- 4 one or the l9-nor derivative thereof(IV) is reduced to the corresponding -01 derivative (X), which, upontreatment in a very mild acid medium readily affords the respective2-formyl-20-cycloethylenedioxy-A -allopregnene derivative (XI).Hydrogenation of this latter compound in the presence of a suitablecatalyst such as platinum oxide affords the2,6-formyl-cycloethylenedioxy-allopregnane derivative (XIII), which uponfurther reduction, preferably with sodium borohydride, afiords thecorresponding Zfi-hydroxymethyl-ZO-cycloethylenedioxy-allopregnanederivative (XV).

Removal of the protective cyclic ketal moiety from the foregoingcompounds as by treatment with a mild acid affords the corresponding20-keto derivatives such as 2- formyl-A -allopregnan-ZO-one (3G1),2fl-formyl-allopregnan-ZO-one (XIV), 2/3-hydroxymethyl-allopregnan-20-one (XVI) and the corresponding 19-nor derivatives thereof.

Treatment of the 2-formyl-20=cycloethylenedioxy-A allopregnene compound(XI) with N-bromosuccinimide in an inert solvent such as carbontetrachloride, furnishes the corresponding 4B-bromo derivative whichupon dehydrohalogenation with a suitable agent such as calcium carbonatein formamide yields the corresponding'Z-formyl- 2O cycloethylenedioxy Apregnadi'ene derivative (XVII). Reduction of this compound affords therespective 2-hydroxymethyl-2O-cycloethylenedioxy-A -pregnadienederivative (XIX). Similarly, hydrolysis in a mild into theZ-hydroXymethyl-A -aIlopregnen-ZO-one derivative (XXII) upon mild acidhydrolysis. v

The hydroxymethyl derivatives described hereinabove are conventionallyacylated in pyridine with an acylatingf agent derived from a hydrocarboncarboxylic acid of less than 12 carbon atoms of the type describedpreviously,

7. thus aflording the corresponding 2-hydrocarbon carboxylicacyloxymethyl derivatives.

The novel 2-methyl derivatives of the present invention are prepared bythe process illustrated by the following equation:

In the above formulas, R has the same meaning as previously set forth.

In practicing the process just outlined, the hereinabove obtainedZ-hydroxymethylene-ZO-cycloethylenedioxy-allopregnan-3-one or the 19-norderivative thereof (III) described above is hydrogenated in the presenceof a suitable catalyst such as palladium on charcoal, in an organicsolvent, as for example, methanol, thus affording the corresponding2a-methyl-20-cycloethylenedioxyallopregnane-3-one compound (XXIII).Reduction of the 3-keto group to the Sfl-hydroxyl and dehydration of theresulting compound (XXIV) by a suitable method, such as the reactionwith tosyl chloride to form the 3B- tosylate which is then treated withcollidine at reflux temperature, thus furnishing the corresponding2-methyl-A allopregnen-ZO-one derivative (XXV).

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention:

Example I A mixture of 5 g. of allopregnan-Sfi-ol-ZO-one, 150 cc. ofanhydrous benzene, 60 cc. of ethyleneglycol distilled sodium hydroxideand 800 mg. of p-toluenesulfonic acid monohydrate was refluxed for 12hours with the use of an adapter for the continuous removal of the waterformed during the reaction. Aqueous sodium bicarbonate solution wasadded to the cooled mixture and the organic phase was separated, washedwith water, dried over anhydrous sodium sulfate and evaporated todryness. The residue crystallized from acetone-hexane to givecycloethylenedioxy-allopregnan-3B-ol.

19-nor-allopregnan-3B-ol-20-one was treated by the above techniquefurnishing ZO-cycloethylene dioxy-19- nor-allopregnan-3B-ol.

Example 11 A solution of 4 g. of20-cycloethylenedioxy-allopregnan-Sfi-ol in 300 cc. of toluene and 80cc. of oyclohexanone was dried by distilling ofl 20 cc. of the solvent.A solution of 4 g. of aluminum isopropoxide dissolved in 28 cc. ofanhydrous toluene was then added and the mixture was refluxed forminutes; 16 cc. of acetic acid were added and the solvents removed bysteam distillation. The product was extracted several times with ethylacetate and the organic extracts washed with 5% hydro- 8: chloric acidsolution, water, 10% sodium carbonate solution and water until neutral,dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization from acetone-hexane aflorded20-cycloethylenedioxy-allopregnan-3-one.

When applying the same method toZO-cycloethylenedioxy-l9-nor-allopregnan-3fi-ol, there was obtained 20-cycloethylenedioxy-19-nor-allopregr1an-3-one.

Example II] To a solution of 3 g. of 20-cycloethylenedioxy-allopregnan-3-one in 60 cc. of anhydrous benzene was added 3 cc.of ethyl formate and 1.3 g. of sodium hydride, suspended in mineral oilwhile cooling and stirring under an atmosphere of nitrogen. The mixturewas stirred for 24 hours at room temperature, hexane was added untilcomplete precipitation, and the solid was collected and dried undervacuum. The crude material was suspended in aqueous hydrochloric acidand was stirred at room temperature for half an hour. The precipitatewas collected, washed with water and dried. Recrystallization frommethylene chloride-hexane gave 2-hydroxymethylene-20-cycloethylenedioxy-allopregnan-3-one.

By the same procedure, there was treated 20-cycloethylenedioxy-l9-nor-allopregnan-3-one, thus furnishing 2- hydroxymethylene 20cycloethylenedioxy-l9-n0r-a1lopregnan-3-one.

Example IV Example V A solution of 1 g. ofZ-methoxymethylene-ZO-cycloethylenedioxy-allopregnan-3-one in 50 cc, oftetrahydrofuran was added over a 30 minutes period to a stirredsuspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydroustetrahydrofuran.

The mixture was re-- fiuxed for 2 hours, then cooled and cautiouslytreated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodiumsulfate was added, the inorganic material filtered off and thoroughlywashed with hot ethyl acetate, the combined organic solutions uponevaporation yielded a crude material, which was purified bycrystallization from acetone-hexane, thus giving-2-methoxymethylene-20-cycloethylenedioxy-allopregnane.

When applying the above technique toZ-methoxymethylene-20-cycloethylenedioxy l9 norallopregnan-3- one, therewas obtainedZ-methoxymethylene-ZOcycloethylenedioxy-l9-nor-allopregnane.

Example VI A solution of l g. ofZ-methoxymethylene-20-cycloethylenedioxy-allopregnane in 50 cc. of etherwas treated with 50 cc. of ether saturated with perchloric acid for 30minutes at C. The solution was then washed with 5% aqueous sodiumbicarbonate solution, and water, dried over sodium sulfate andevaporated to dryness. Recrystallization from acetone-hexane afiorded2a-formyl-20- cycloethylenedioxy-allopregnane.

By the same procedure, there was treated Z-methoxymethylene 20cycloethylenedioxy-19-nor-allopregnane, thus giving2a-formyl-20-cycloethylenedioxy-19-nor-allopregnane.

Example VI] A solution of 2 g. of sodium borohydride in 30 cc. ofmethanol was added with stirring to a solution of 2 g. of2a-formyl-20-cycloethylenedioxy-allopregnane in 40 cc. oftetrahydrofuran. The mixture was kept at room temperature overnight, theexcess reagent was decomposed by addition of acetic acid, the resultingsolution concentrated to small volume in vacuo and diluted with water.The product was extracted with ethyl acetate, the extract washed withwater, dried and evaporated. Crystallization of the solid fromacetone-hexane gave 2a-hydroxymethyl-ZO-cycloethylenedioxyallopregnane.

Upon treatment of 2a-formyl-20-cycloethylenedioxyl9-nor-allopregnane bythe same procedure, there was obtained2ot-hydroxymethyl-20-cycloethylenedioxy l9-norallopregnane.

Example VIII 5 g. of2-methoxymethylene-20-cycloethylenedioxyallopregnan-3-one, obtained inaccordance with Example IV, were reduced following the proceduredescribed in Example VII, thus furnishing 2-methoxymethylene-20-cycloethylenedioxy-allopregnan-3,B-ol.

By the same procedure, Z-methoxymethylene-20-cycloethylenedioxy-l9-nor-allopregnan-3-one was reduced to2-methoxymethylene-ZO-cycloethylenedioxy-19 nor-allopregnan-3fi-ol.

Example IX 4 g. of2-methoxymethylene-20-cycloethylenedioxyallopregnan-Elfi-ol in 70 cc. ofwarm methanol were treated with 0.25 cc. of concentrated hydrochloricacid and the resulting mixture was allowed to stand for 3 minutes. Thenit was poured into a large excess of water, the formed precipitatefiltered ofr, washed and recrystallized from acetone, thus atfording2-formyl-20- cycloethylenedioxy-n -allopreguene.

Treating by the same procedure, Z-methoxymethylene-20-cycloethylenedioxy-19-nor-allopregnan-3B-ol, there was obtained2-formyl-20-cycloethylenedioxy-l9-nor-A -allopregnene.

Example X A solution of 2 g. of '2-formyl-20-cycloethylenedioxy- A-allopregnene obtained in accordance with Example IX in 100 cc. of ethylacetate was shaken with 100 mg. of platinum oxide catalyst in a hydrogenatmosphere until the gas uptake corresponded to one mol. The catalystwas filtered off and the filtrate evaporated to dryness.

Recrystallization from acetone-hexane yielded 2,B-formyl-20-cycloethylenedioxy-allopregnane.

Upon treatment of 2-formyl-20-cycloethylenedioxy 19 nor-n -allopregneneby the same technique, there was formed 25 formyl 20cycloethylenedioxy-19-nor-allopregnane.

Example XI 2/3-formyl-20-cycloethylenedioxy-allopregnane and 2B-formyI-ZO-cycloethylenedioxy l9 nor-allopregnane were reduced followingthe technique described in Example VII, furnishing respectively2,8-hydroxymethyl-20-cycloethylenedioxy-allopregnane andZB-hydroxymethyl-ZO- cycloethylenedioxy-19-nor-allopregnane.

By the same procedure was treated Z-formyI-ZO-cycloethylenedioxy-A-allopregnene and 2-formyl-20-cycloethylenedioxy-19-nor-A allopregneneaffording Z-hydroxymethyl-20-cycloethylenedioxy-A -allopregnene and2-hydroxymethyl-20-cycloethylenedioxy 19 nor A allopregnene.

' Example XII 4.2 g. of 2forrnyl-20-cycloethylenedioxy-n -allopregneneobtained in accordance with Example IX in 200 cc. of carbontetrachloride was irradiated with a GE sun lamp and refluxed with 2.7 g.of N-bromosuccinimide for 30 minutes. The mixture was filteredtoeliminate the succinimide that was formed during the reaction. Thefiltrate was evaporated to dryness under reduced pressure.Recrystallization from methylene-chloride-hexane gave2-formyl-4fl-bromo-20 cycloethylenedioxy A allopregnene.

1 g. of the above compound was refluxed with 1 g.

of calcium carbonate and 50 cc. of dimethylformarnide for 30 minutes.evaporated under reduced pressure and the residue crystallized fromacetone-hexane to afford 2-formyl-20-cycloethylenedioxy-M: -pregnadiene.

2-formyl-20-cycloethylenedioxy-19-nor A allopregnene was treated by theabove described technique, furnishing 2 formyl 20cycloethylenedioxy-19-nor-A pregnadiene.

Example XIII 2-formyl-2O-cycloethylenedioxy-A -pregnadiene and2-formyl-20-cycloethylenedioxy-19-nor-A pregnadiene were reducedfollowing the technique described in Example VII, furnishingrespectively 2-hydroxymethyl-20- cycloethylenedioxy-A -pregnadiene and2-hydroxymethyl-20-cycloethylenedioxy-19-nor-A -pregnadiene.

Example XIV 7 g. of2-hydroxymethylene-ZO-cycloethylenedioxyallopregnan-3-one obtained inaccordance with Example 111 were dissolved in 300 cc. of methanol andmixed with 2.5 g. or a 10% palladium on characoal catalyst.

The mixture was hydrogenated at atmospheric pressure, at approximately25 C. until the absorption of hydrogen ceased. The catalyst was removedby filtration, l g. of potassium hydroxide in 5 cc. of water was addedto the solution which was then kept for one hour at room temperature; 2cc. of acetic acid were added, the solvent was I Example XV I2a-methyl-Z0-cycloethylenedioxy-allopregnan-3-one and The mixture wasfiltered, the solvent 11 2amethyl-20-cycloethylenedioxy-19-nor-allopregnan-3- one were reduced inaccordance with Example VII furnishing respectively2a-methyl-20-cycloethylenedioxyallopregnan-3fi-ol and2mmethyl-ZO-cycloethylenedioxy- 19-nor-allopregnane-313-ol.

Example X VI A solution of g. of2a-methyl-20-cycloethylenedioxyallopregnan-3fi-ol in 25 cc. of pyridinewas cooled to 0 C. Under stirring there was added 1.3 g. of tosylchloride, the mixture was kept for 16 hours at 0 C., diluted with 100cc. of chloroform, washed with dilute hydrochloric acid, water, aqueoussodium bicarbonate solution and again with water, dried over anhydroussodium sulfate and then evaporated to dryness under reduced pressure.Thus there was obtained the crude2u-methyl-allopregnan-3fiol-20-0ne-3-tosylate.

The total crude compound was refluxed with 60 cc. of y-collidine for 90minutes under anhydrous conditions. The solution was cooled andfiltered. The filtrate was diluted with ether, washed with dilutehydrochloric acid, sodium carbonate solution and water. The driedextract was evaporated and the residue was chromatographed on neutralalumina. Crystallization of the solid fractions from acetone-hexaneafforded 2-methyl-A -allopregnen-ZO-one.

Treatment of Za-methyl-20-cycloethylenedioxy-19-norallopregnane by thesame procedure yielded 2-methy1-19- nor-A -a1lopregnen-20-one.

Example XVII 500 mg. of 2a-formyl-20-cycloethylenedioxy-allopregnanewere dissolved in 30 cc. of acetone and treated with 50 mg. ofp-toluenesulfonic acid, the reaction mixture was kept at roomtemperature overnight. It was then poured into ice water, extracted withethyl acetate and the organic extract washed with water to neutral,dried and evaporated to dryness. Addition of ether gave 20:-formyl-allopregnan-ZO-one.

, Following the above technique, there were treated the startingcompounds listed below, thus furnishing the respcctive productshereinafter set forth:

Starting compound Product Qa-formyl-19-n0r-allopregnan-20- 2-8;;yI'A-alIoprcgnen-ZO-One.

2-iormyl-19-nor-A -allopregncn-20- 2fl i%iinylallopregnen20-one.

ZB-Iormly-l9-nor-allopregnan-20- 2& r 1 ny1-A -pregnadien-2(lone.

2-fo1'myl-19-nor-A -pregnadicn-20- 2aglgidroxymethyl-allopregnanne.2a-hydroxymethyll9-norallopregnan-ZO-one.

2-11ydroxymethyl-N-allopregnen- 20one.

2hydroxymethyHQ-nor-A all0pregnen-20-onc.

,B-hydroxymethyl-allopregnan- 20-one.

QB-hydroxymethyl-lQ-noral1opregnan-20-one.

Z-hydroxymethyl-N- pregnadien-QOone.

2-hydroxyrnethyl-lQ-nor-A prcgnadicn-20-onc.

Example XVIII A mixture of l g. of 2a-hydroxymethyl-allopregnan- 20-one;cc. of pyridine, and 2 cc. of acetic anhydride was kept overnight atroom temperature.

The reaction mixture was then poured into ice waterythe resultingprecipitate filtered oif, washed with water, dried under vacuum andrecrystallized from ethyl acetate-hexane, thus giving2a-acetoxymethyl-allopregnan-ZO-one.

The starting compounds hereinafter listed were treated following theabove technique furnishing the corresponding products set forth below:

Starting compound Product allopregnan-Ztlone. allopregnan-20-one.Z-hydroxymethyl-Nallopregnen- 2-aeetoxymethyl-N-allopregnen- 2Erone.20-one. Z-hydroxymethyl-lQ-nonA' Z-ncetoxymethyldQ-nor-Aallopregnen-20-one. allopregnen-20-one. Z-hydroxymcthyl-N-2-acetoxymethy1-A preguadicn-Ztkone. prcgnndicn-Zdone.2-hydr0xymcthyl-19nor A 2-acetoxymethyl-l9-nor-A pregnadien-QMne.25acctoxymethyl-a11opregnan-20- one.Zfl-acetoxymethyl-lQ-noralloprcgnan-20'one.

pregnadien-20-one. ZB-hydrowmethyl-allopregnan-20- onQB-hydroxymethyl-lQ-noralloprcgnan-ZO-one.

The above starting compounds were treated following the hereinabovedescribed procedure except that acetic anhydride was substituted bypropionic anhydride, caproic anhydride, cyclopentylpropionic anhydrideand benzoyl chloride, thus yielding the corresponding propionoxymethyl,caproxymethyl, cyclopentylpropionoxymethyl and benzoyloxymethylderivatives.

We claim:

1. A compound of the following formula:

CHa

wherein R is selected from the group consisting of hydrogen and methyl;R is selected from the group consisting of formyl (-CHO) and the group-CH --'OR wherein R is a member of the group consisting of hydrogen anda hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

8. 2-formyl-A -pregnadien-2O-one.

9. 2-formyl-19-nor-A -pregnadien-2O-one.

10. Z-hydroxymethyl-A -pregnadien-ZO-one.

11. Z-hydroxymethyl-l 9-nor-A -pregnadien-2 O-one.

=12. 2-acetoxymethyl-A -pregnadien-2Gone.

14 13. A compound of the following formula: a hydrocarbon carboxylicacyl group of less than 12 carbon atoms. 14.Za-formyl-allopregnan-ZO-one. 15. ZB-formyl-allopregnan-ZO-one. 162u.-formy1-19-nor-allopregnan-20-one.

17. 2B-formyl-l9-nor-allopregnan-20-one. 18.2a-hydroxymethyl-allopregnan-ZO-one. R 19. 28-lhydroxymethyl-allopregnan-20-one. R1 NW 20. 2a-hydroxymethy-l-19-nor-allopregnan-20-one. 10 21.2fi-hydroxymethy1-19-nor-a1lopregnan-20-one.

22. 2u-acetoxymethyl-allopregnan-20-one. 23.2,8-acetoxymethyl-allopregnan-20-one. wherein R is selected from thegroup consisting of hydro- 24. Z-methyl-A -a1lopregnen-20-one. gen andmethyl; R is selected from the group consisting 25. Z-methyl-19-nor-A-allopregnen-20-one. of formyl (-CHO) and the group -CH -OR wherein 15 Ris a member of the group consisting of hydrogen and No references cited.

1. A COMPOUND OF THE FOLLOWING FORMULA: